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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1993 Feb 15;90(4):1411–1415. doi: 10.1073/pnas.90.4.1411

Combined use of an immunotoxin and cyclosporine to prevent both activated and quiescent peripheral blood T cells from producing type 1 human immunodeficiency virus.

K D Bell 1, O Ramilo 1, E S Vitetta 1
PMCID: PMC45883  PMID: 8434001

Abstract

Two different populations of infected T cells are present in human immunodeficiency virus (HIV)-infected individuals: activated cells that produce virions and quiescent cells that harbor the viral genome but are unable to produce virus unless they are activated. Using an in vitro model of acute HIV infection, we have evaluated the effect of depleting activated T cells with an immunotoxin and subsequently inhibiting activation of quiescent T cells with an immunosuppressive agent. CD25 (Tac, p55), the alpha chain of the interleukin 2 receptor, is expressed on activated, but not quiescent, T cells. An anti-CD25-ricin A chain immunotoxin eliminated activated, CD25+ HIV-infected cells and, thereby, inhibited viral production by these cells. Subsequent addition of cyclosporine to the residual CD25- cells prevented their activation and thereby suppressed their ability to produce virus and to propagate the infection to uninfected T cells.

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Selected References

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  1. Allain J. P., Laurian Y., Paul D. A., Verroust F., Leuther M., Gazengel C., Senn D., Larrieu M. J., Bosser C. Long-term evaluation of HIV antigen and antibodies to p24 and gp41 in patients with hemophilia. Potential clinical importance. N Engl J Med. 1987 Oct 29;317(18):1114–1121. doi: 10.1056/NEJM198710293171804. [DOI] [PubMed] [Google Scholar]
  2. Andrieu J. M., Even P., Venet A., Tourani J. M., Stern M., Lowenstein W., Audroin C., Eme D., Masson D., Sors H. Effects of cyclosporin on T-cell subsets in human immunodeficiency virus disease. Clin Immunol Immunopathol. 1988 May;47(2):181–198. doi: 10.1016/0090-1229(88)90071-2. [DOI] [PubMed] [Google Scholar]
  3. Benn S., Rutledge R., Folks T., Gold J., Baker L., McCormick J., Feorino P., Piot P., Quinn T., Martin M. Genomic heterogeneity of AIDS retroviral isolates from North America and Zaire. Science. 1985 Nov 22;230(4728):949–951. doi: 10.1126/science.2997922. [DOI] [PubMed] [Google Scholar]
  4. Birx D. L., Redfield R. R. HIV vaccine therapy. Int J Immunopharmacol. 1991;13 (Suppl 1):129–132. doi: 10.1016/0192-0561(91)90134-s. [DOI] [PubMed] [Google Scholar]
  5. Bukrinsky M. I., Stanwick T. L., Dempsey M. P., Stevenson M. Quiescent T lymphocytes as an inducible virus reservoir in HIV-1 infection. Science. 1991 Oct 18;254(5030):423–427. doi: 10.1126/science.1925601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chaudhary V. K., Mizukami T., Fuerst T. R., FitzGerald D. J., Moss B., Pastan I., Berger E. A. Selective killing of HIV-infected cells by recombinant human CD4-Pseudomonas exotoxin hybrid protein. Nature. 1988 Sep 22;335(6188):369–372. doi: 10.1038/335369a0. [DOI] [PubMed] [Google Scholar]
  7. Deen K. C., McDougal J. S., Inacker R., Folena-Wasserman G., Arthos J., Rosenberg J., Maddon P. J., Axel R., Sweet R. W. A soluble form of CD4 (T4) protein inhibits AIDS virus infection. Nature. 1988 Jan 7;331(6151):82–84. doi: 10.1038/331082a0. [DOI] [PubMed] [Google Scholar]
  8. Dummer J. S., Erb S., Breinig M. K., Ho M., Rinaldo C. R., Jr, Gupta P., Ragni M. V., Tzakis A., Makowka L., Van Thiel D. Infection with human immunodeficiency virus in the Pittsburgh transplant population. A study of 583 donors and 1043 recipients, 1981-1986. Transplantation. 1989 Jan;47(1):134–140. doi: 10.1097/00007890-198901000-00030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Engert A., Martin G., Amlot P., Wijdenes J., Diehl V., Thorpe P. Immunotoxins constructed with anti-CD25 monoclonal antibodies and deglycosylated ricin A-chain have potent anti-tumour effects against human Hodgkin cells in vitro and solid Hodgkin tumours in mice. Int J Cancer. 1991 Sep 30;49(3):450–456. doi: 10.1002/ijc.2910490324. [DOI] [PubMed] [Google Scholar]
  10. Finberg R. W., Wahl S. M., Allen J. B., Soman G., Strom T. B., Murphy J. R., Nichols J. C. Selective elimination of HIV-1-infected cells with an interleukin-2 receptor-specific cytotoxin. Science. 1991 Jun 21;252(5013):1703–1705. doi: 10.1126/science.1904628. [DOI] [PubMed] [Google Scholar]
  11. Fischl M. A., Richman D. D., Grieco M. H., Gottlieb M. S., Volberding P. A., Laskin O. L., Leedom J. M., Groopman J. E., Mildvan D., Schooley R. T. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):185–191. doi: 10.1056/NEJM198707233170401. [DOI] [PubMed] [Google Scholar]
  12. Fisher R. A., Bertonis J. M., Meier W., Johnson V. A., Costopoulos D. S., Liu T., Tizard R., Walker B. D., Hirsch M. S., Schooley R. T. HIV infection is blocked in vitro by recombinant soluble CD4. Nature. 1988 Jan 7;331(6151):76–78. doi: 10.1038/331076a0. [DOI] [PubMed] [Google Scholar]
  13. Geppert T. D., Lipsky P. E. Activation of T lymphocytes by immobilized monoclonal antibodies to CD3. Regulatory influences of monoclonal antibodies to additional T cell surface determinants. J Clin Invest. 1988 May;81(5):1497–1505. doi: 10.1172/JCI113481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ghetie V., Slaughter C., Wheeler H. T., Uhr J. W., Vitetta E. S. CD4 peptide-protein conjugates, but not recombinant human CD4, bind to recombinant gp120 from the human immunodeficiency virus in the presence of serum from AIDS patients. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5690–5693. doi: 10.1073/pnas.88.13.5690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ghetie V., Thorpe P., Ghetie M. A., Knowles P., Uhr J. W., Vitetta E. S. The GLP large scale preparation of immunotoxins containing deglycosylated ricin A chain and a hindered disulfide bond. J Immunol Methods. 1991 Sep 13;142(2):223–230. doi: 10.1016/0022-1759(91)90110-2. [DOI] [PubMed] [Google Scholar]
  16. Hersh E. M. Current status of immunotherapy of patients with HIV-infection. Int J Immunopharmacol. 1991;13 (Suppl 1):9–18. doi: 10.1016/0192-0561(91)90119-r. [DOI] [PubMed] [Google Scholar]
  17. Ho D. D. HIV-1 viraemia and influenza. Lancet. 1992 Jun 20;339(8808):1549–1549. doi: 10.1016/0140-6736(92)91321-x. [DOI] [PubMed] [Google Scholar]
  18. Hussey R. E., Richardson N. E., Kowalski M., Brown N. R., Chang H. C., Siliciano R. F., Dorfman T., Walker B., Sodroski J., Reinherz E. L. A soluble CD4 protein selectively inhibits HIV replication and syncytium formation. Nature. 1988 Jan 7;331(6151):78–81. doi: 10.1038/331078a0. [DOI] [PubMed] [Google Scholar]
  19. Jackson G. G., Perkins J. T., Rubenis M., Paul D. A., Knigge M., Despotes J. C., Spencer P. Passive immunoneutralization of human immunodeficiency virus in patients with advanced AIDS. Lancet. 1988 Sep 17;2(8612):647–652. doi: 10.1016/s0140-6736(88)90468-0. [DOI] [PubMed] [Google Scholar]
  20. Karpas A., Lowdell M., Jacobson S. K., Hill F. Inhibition of human immunodeficiency virus and growth of infected T cells by the immunosuppressive drugs cyclosporin A and FK 506. Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):8351–8355. doi: 10.1073/pnas.89.17.8351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Marasco W. A., Bagley J., Zani C., Posner M., Cavacini L., Haseltine W. A., Sodroski J. Characterization of the cDNA of a broadly reactive neutralizing human anti-gp120 monoclonal antibody. J Clin Invest. 1992 Oct;90(4):1467–1478. doi: 10.1172/JCI116014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Phillips A., Wainberg M. A., Coates R., Klein M., Rachlis A., Read S., Shepherd F., Vellend H., Walmsley S., Halloran P. Cyclosporine-induced deterioration in patients with AIDS. CMAJ. 1989 Jun 15;140(12):1456–1460. [PMC free article] [PubMed] [Google Scholar]
  23. Pincus S. H., Wehrly K., Chesebro B. Treatment of HIV tissue culture infection with monoclonal antibody-ricin A chain conjugates. J Immunol. 1989 May 1;142(9):3070–3075. [PubMed] [Google Scholar]
  24. Prince A. M., Horowitz B., Baker L., Shulman R. W., Ralph H., Valinsky J., Cundell A., Brotman B., Boehle W., Rey F. Failure of a human immunodeficiency virus (HIV) immune globulin to protect chimpanzees against experimental challenge with HIV. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6944–6948. doi: 10.1073/pnas.85.18.6944. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Redfield R. R., Birx D. L., Ketter N., Tramont E., Polonis V., Davis C., Brundage J. F., Smith G., Johnson S., Fowler A. A phase I evaluation of the safety and immunogenicity of vaccination with recombinant gp160 in patients with early human immunodeficiency virus infection. Military Medical Consortium for Applied Retroviral Research. N Engl J Med. 1991 Jun 13;324(24):1677–1684. doi: 10.1056/NEJM199106133242401. [DOI] [PubMed] [Google Scholar]
  26. Scharpe S., De Meester I., Hendriks D., Vanhoof G., van Sande M., Vriend G. Proteases and their inhibitors: today and tomorrow. Biochimie. 1991 Jan;73(1):121–126. doi: 10.1016/0300-9084(91)90084-e. [DOI] [PubMed] [Google Scholar]
  27. Schmidt A., Hennighausen L., Siebenlist U. Inducible nuclear factor binding to the kappa B elements of the human immunodeficiency virus enhancer in T cells can be blocked by cyclosporin A in a signal-dependent manner. J Virol. 1990 Aug;64(8):4037–4041. doi: 10.1128/jvi.64.8.4037-4041.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Schreiber S. L., Crabtree G. R. The mechanism of action of cyclosporin A and FK506. Immunol Today. 1992 Apr;13(4):136–142. doi: 10.1016/0167-5699(92)90111-J. [DOI] [PubMed] [Google Scholar]
  29. Skowron G. Treatment of HIV infection: the antiretroviral nucleoside analogues. Nucleoside analogues: monotherapy. Hosp Pract (Off Ed) 1992 Aug;27 (Suppl 2):5–13. doi: 10.1080/21548331.1992.11705595. [DOI] [PubMed] [Google Scholar]
  30. Smith D. H., Byrn R. A., Marsters S. A., Gregory T., Groopman J. E., Capon D. J. Blocking of HIV-1 infectivity by a soluble, secreted form of the CD4 antigen. Science. 1987 Dec 18;238(4834):1704–1707. doi: 10.1126/science.3500514. [DOI] [PubMed] [Google Scholar]
  31. Stevenson M., Stanwick T. L., Dempsey M. P., Lamonica C. A. HIV-1 replication is controlled at the level of T cell activation and proviral integration. EMBO J. 1990 May;9(5):1551–1560. doi: 10.1002/j.1460-2075.1990.tb08274.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Thorpe P. E., Wallace P. M., Knowles P. P., Relf M. G., Brown A. N., Watson G. J., Knyba R. E., Wawrzynczak E. J., Blakey D. C. New coupling agents for the synthesis of immunotoxins containing a hindered disulfide bond with improved stability in vivo. Cancer Res. 1987 Nov 15;47(22):5924–5931. [PubMed] [Google Scholar]
  33. Till M. A., Ghetie V., Gregory T., Patzer E. J., Porter J. P., Uhr J. W., Capon D. J., Vitetta E. S. HIV-infected cells are killed by rCD4-ricin A chain. Science. 1988 Nov 25;242(4882):1166–1168. doi: 10.1126/science.2847316. [DOI] [PubMed] [Google Scholar]
  34. Till M. A., Zolla-Pazner S., Gorny M. K., Patton J. S., Uhr J. W., Vitetta E. S. Human immunodeficiency virus-infected T cells and monocytes are killed by monoclonal human anti-gp41 antibodies coupled to ricin A chain. Proc Natl Acad Sci U S A. 1989 Mar;86(6):1987–1991. doi: 10.1073/pnas.86.6.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Traunecker A., Lüke W., Karjalainen K. Soluble CD4 molecules neutralize human immunodeficiency virus type 1. Nature. 1988 Jan 7;331(6151):84–86. doi: 10.1038/331084a0. [DOI] [PubMed] [Google Scholar]
  36. Wainberg M. A., Dascal A., Blain N., Fitz-Gibbon L., Boulerice F., Numazaki K., Tremblay M. The effect of cyclosporine A on infection of susceptible cells by human immunodeficiency virus type 1. Blood. 1988 Dec;72(6):1904–1910. [PubMed] [Google Scholar]
  37. Waldmann T. A., Pastan I. H., Gansow O. A., Junghans R. P. The multichain interleukin-2 receptor: a target for immunotherapy. Ann Intern Med. 1992 Jan 15;116(2):148–160. doi: 10.7326/0003-4819-116-2-148. [DOI] [PubMed] [Google Scholar]
  38. Yefenof E., Abboud G., Epszteyn S., Vitetta E. S. Treatment of premalignancy: prevention of lymphoma in radiation leukemia virus-inoculated mice by cyclosporin A and immunotoxin. Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):728–732. doi: 10.1073/pnas.89.2.728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Yefenof E., Epszteyn S., Kotler M. Quantitation, in vitro propagation, and characterization of preleukemic cells induced by radiation leukemia virus. Cancer Res. 1991 Apr 15;51(8):2179–2184. [PubMed] [Google Scholar]
  40. Zack J. A., Arrigo S. J., Weitsman S. R., Go A. S., Haislip A., Chen I. S. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell. 1990 Apr 20;61(2):213–222. doi: 10.1016/0092-8674(90)90802-l. [DOI] [PubMed] [Google Scholar]
  41. Zack J. A., Haislip A. M., Krogstad P., Chen I. S. Incompletely reverse-transcribed human immunodeficiency virus type 1 genomes in quiescent cells can function as intermediates in the retroviral life cycle. J Virol. 1992 Mar;66(3):1717–1725. doi: 10.1128/jvi.66.3.1717-1725.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Zarling J. M., Moran P. A., Haffar O., Sias J., Richman D. D., Spina C. A., Myers D. E., Kuebelbeck V., Ledbetter J. A., Uckun F. M. Inhibition of HIV replication by pokeweed antiviral protein targeted to CD4+ cells by monoclonal antibodies. Nature. 1990 Sep 6;347(6288):92–95. doi: 10.1038/347092a0. [DOI] [PubMed] [Google Scholar]

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